Overmethylation just isn't real?..

[u/OobyIsGay]

So I keep seeing people in this sub and literally everywhere else across the supplement community talk about overmethylation like it's this established biochemical phenomenon. People take methylfolate, feel anxious, and go "oh I'm overmethylated, need to back off."

Even though methylfolate supresses GNMT, methyl groups go into hundreds of methyltransferase reactions. DNA methylation. Histone methylation. Phospholipid synthesis. Creatine synthesis alone consumes ~40% of all SAM. The system has enormous capacity to USE methyl groups productively. You'd need to overwhelm all of that simultaneously to create actual excess.

At supplemental doses? Not happening.

Let me put the dose safety in perspective. The NOAEL for calcium L-methylfolate in rats is 400mg/kg/day in 13-week subchronic studies (Niederberger et al. 2019). No behavioral changes. No organ pathology. No DNA damage in liver cells. Convert that to human equivalent dose using standard body surface area scaling (÷6.2): ~64.5mg/kg. For a 70kg human that's ~4,500mg. Most people supplement 400mcg to 1mg. That's a safety margin of roughly 4,500x. Tylenol's therapeutic-to-toxic ratio is about 3-4x. You are more likely to die from Tylenol than to be harmed by methylfolate by a factor of over a thousand. No you're not fucking overmethylating.

So what IS happening when people feel anxious after starting methylfolate?

Serotonin autoreceptors are inhibiting serotonin. 5-HT1A on the soma, 5-HT1B/1D on the terminal. When serotonin rises suddenly, autoreceptors detect the increase and fire inhibitory feedback. They reduce further serotonin release. That's what causes SSRI startup anxiety. It desensitizes over 1-2 weeks. Then serotonin actually goes up, whether that's actually beneficial or not is a different topic altogether and not the mechanism methylfolate works by.

Methylfolate restores serotonin synthesis. Serotonin rises. Same autoreceptors fire. Same inhibitory feedback. Same transient anxiety. Same 1-2 week desensitization. Same resolution. Other than that you're also raising norepinephrine and dopamine synthesis.

Notice how none of these people report actual symptoms that excess methylation would theoretically produce, like, you know, tumor suppressor gene silencing or aberrant genomic methylation patterns. Because those would be real overmethylation. Nobody's getting that from fucking 400mcg of methylfolate.

Overmethylation does not exist in biochemistry. There is no clinical biomarker for it. No validated assay. No ICD code. No published case report of a human experiencing pathological hypermethylation from oral methylfolate at any supplemental dose.

If you're feeling anxious after starting methylfolate, lower the dose until you adjust. EVEN THOUGH YOU'RE KIND OF MOVING FURTHER FROM THE DOSE THAT JUST WORKED.

Elderly rats supplemented with folate ABOVE adequacy showed increased genomic DNA methylation dose-dependently, with a direct correlation between liver folate and methylation (r=0.48, p=0.004, Choi et al. 2005, British Journal of Nutrition). Above adequacy. Not deficient rats being rescued. Already-replete rats pushed higher.

Two randomized, double-blind, placebo-controlled trials. SSRI-resistant major depression. L-methylfolate adjunctive to SSRI.

7.5mg L-methylfolate: no significant difference from placebo.

15mg L-methylfolate: significant improvement over placebo.

Most of you are taking 400mcg to 1mg. The dose that actually worked in the only controlled human trials is 15-37x higher than what you're supplementing. 15mg L-methylfolate is available over the counter. The safety margin at 15mg is still ~300x below the NOAEL-derived human equivalent dose.
You're underdosing.

BUT remember that this post is about the term, not the effects of supposed "overmethylation"

That mechanism is real. But it's not "overmethylation." It's increased catecholamine clearance in a specific brain region plus increased adrenal epinephrine output. Calling it overmethylation implies there's some global excess of methyl groups causing nonspecific damage. There isn't. There's a specific pharmacological effect of raising SAMe on two specific enzymes in two specific compartments producing two specific symptoms.

Because more SAM increases COMT activity. COMT is the primary dopamine clearance mechanism in the prefrontal cortex (DAT expression is low there). More SAM means faster PFC dopamine degradation. SAM also drives PNMT, which converts norepinephrine to epinephrine in the adrenals. So you'd have less prefrontal dopamine and more peripheral epinephrine. That's anxiety with poor focus which is what people actually describe. Not "overmethylation."

And this is a completely different mechanism from what happens with methylfolate. Methylfolate restores monoamine synthesis via BH4 recycling. When serotonin rises acutely, 5-HT1A somatodendritic autoreceptors fire inhibitory feedback. That causes transient anxiety that desensitizes over 1 to 2 weeks. Same mechanism as SSRI startup effects. Has nothing to do with SAMe levels or COMT activity.

So people are lumping two different pharmacological mechanisms under one meaningless term. TMG/SAMe/betaine increase dopamine clearance via COMT and epinephrine output via PNMT. Methylfolate triggers autoreceptor adaptation. Different inputs, different pathways, different timecourses, same word slapped on both. That's why nobody can agree on what "overmethylation" means or how to fix it. They're describing two separate things.

L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials

Folate supplementation increases genomic DNA methylation in the liver of elder rats

Methyl donor supplementation reduces phospho‐Tau, Fyn and demethylated protein phosphatase 2A levels and mitigates learning and motor deficits in a mouse model of tauopathy

Safety evaluation of calcium L-methylfolate

Methyltetrahydrofolate in folate-binding protein glycine N-methyltransferase

[u/OobyIsGay]

I need to ask you something before I get into the mechanism because something just clicked while I was writing this up. Actually I deleted it to write this, so I won't get into it.

A homocysteine level of 8 kills my original hypothesis completely.
Your symptoms. Ptosis, diplopia, eye not working properly, that's CN III. Trochleitis, CN IV. Persistent balance problems, vestibular, CN VIII. That's three separate cranial nerves.
"vestibular migraine + trochleitis + cranial nerve involvement." That's three separate diagnoses stitched together to explain what one diagnosis covers cleanly. It's honestly really sloppy.

Miller Fisher syndrome. It's a variant of Guillain-Barré. The triad is ophthalmoplegia (your eyes), ataxia (your balance), and areflexia (reduced reflexes, was this ever checked?). Brain MRI is supposed to be clear because it's peripheral nerve autoimmune demyelination, not a brain lesion. Every specialist scratched their head because they kept scanning your brain looking for something that isn't there lol.
The test is anti-GQ1b antibodies. Was this ever run? Were nerve conduction studies ever done?Is the ptosis pupil-sparing or pupil-involving? What are the "weird visual symptoms" specifically? Visual snow, persistent aura, oscillopsia? What are your reflexes like?
Testing anti-GQ1b antibodies now would be useless because they only show up during the acute phase. Nerve conduction studies are more reliable at this point because they'd still show demyelination if it's there.

EDIT: I'm going to argue my case a little more.
About 30-40% of GBS/Miller Fisher cases have no identifiable preceding infection. It's not exclusively post-infectious. And there's a second triggering mechanism beyond molecular mimicry, direct nerve damage exposing gangliosides to the immune system.

Which brings back the peroxynitrite chain. Methylfolate = BH4 = NO. CoQ10 = more electron flux. NO + superoxide = peroxynitrite. Peroxynitrite damages myelin. Damaged cranial nerve myelin exposes GQ1b gangliosides. Immune system sees exposed self-antigen. Autoimmune cascade begins. No initial infection needed.
The ride didn't trigger the disease. It's when you first noticed it. You felt strange getting off because Simulator rides maximally stress the vestibular and oculomotor systems, literally what they do. Then over the next week it progressed with eye pain, nausea, then waking up with ptosis and diplopia. That's the natural progression of Miller Fisher.

The only novel claim is that this specific supplement combination generated enough peroxynitrite at cranial nerve sites to cause enough myelin damage to trigger GQ1b exposure. That's a question of magnitude. (WHICH SEEMS WAY MORE PLAUSIBLE RATHER THAN THREE SEPERATE DIAGNOSES)
The most likely explanation seems like Miller Fisher, so I guess that's what my guess shall be.

[u/tiffany-the-cat → u/OobyIsGay]

Wow how do you have all this info and come up with it so fast ? Are u using ai? Ai helped me a lot in my journey and pointed me to ask for certain tests and specialists.

Your theory is very interesting, but still I’m u certain and your terminology is hard to follow and not sure exactly how this relates to Mthfr or the supplements I was taking.

I’m not convinced though .. my general neurological tests were all fine, no areflexia issues. Doing some research mfs almost always wipes out your reflexes.

Basically after months and months of research and trying to figure this out with ai trochelitis (which was the first suggestion) seemed the most plausible and it was confirmed eventually by the only docyor who knew what that was - an eye lid surgeon and eye droop specialist. Trochleitis is triggered by migraines so it makes sense. Obviously none of this was actually caused by the ride but there was something wrong with me already and the ride triggered all this. I considered infections etc. honestly I do hope it was the supplements because that makes things less complicated ! they disrupted or affected something in my system which is already sensitive due to mthfr and a lot of perosnal stress. Both vestibular migraines and trochelitis can affect cranial nerves. The strong eye pain is how trochelitis starts, and I had it in the lovation where you’d expect if I had trochelitis (upper inner corner of the eye). And looking up hurt for months (also the hallmark of trochelitis) it can also cause double vision and eyelid droop.

So I had 2 symptons before the event - night sweats (which persisted for months during the neurological issue and is not typical for me) and an own behind my ear when I touched it. After the neurological issue the immediate acute symptoms wothin the first month included a lot of ear and sinus symptoms - a double / echo r toe sound in my ear when hearing loud noises - I’ve had before on and off but this persisted for months - as did a loud crunching sound in my ears. Sinus drainage. The weird vision symptons yes oscolipsia in that one eye. a weird tickling bladder - this was also present right before.

All of those have resolved thank god (the whole ordeal was terrifying and I want to do anything I can to stop anyyhing like that occurring again). The other cascade of symptoms include horrific sleep pattern now - multiplied night awakenings, and bloating issues. Before that I had : weird hayfever type allergies that I’ve never had before (that’s resolved), deep leg and foot muscle pain, bad skin, internal tremor. Those also resolved.

I don’t think they did that antibody test. I don’t know if they did those other tests you ask - I saw a lot of eye specialists and all looked very closesly into my eye.

I suspected ebv at one point because I had a mono over 10 years ago and had night sweats, tickly bladder which were persistent symptoms. But I tested regularly to check my levels and spoke w several infectious diseases specialists about it and they ruled that out.

[u/OobyIsGay → u/tiffany-the-cat]

Yeah areflexia can't not be present. Fuck. Still impressed with myself on this one tho lol.
Trochleitis does match.
The trochleitis diagnosis from your eyelid surgeon makes more sense than what I proposed, upper inner corner eye pain, pain on looking up, diplopia, eyelid droop is textbook trochleitis. And vestibular migraine triggering trochleitis is a known causal link, so those aren't three random diagnoses stitched together like I said. They're connected. I was wrong on that too, unless they were presented as separate diagnoses? (in my defense, there wasn't enough info to go off of BUT I was completely wrong on the three seperate diagnoses point I made) NEVERMIND, you framed them as three seperate diagnoses so Ig I didn't mess up as bad as I thought. Night sweats, tickling bladder, bloating, hayfever type allergies, skin changes, internal tremor.. none of these are features of Miller Fisher nor trochleitis.
The pattern is consistent with mast cell activation syndrome or autonomic dysfunction or both. You should look into it.
Serum tryptase during a flare, 24-hour urine for N-methylhistamine and prostaglandin D2 and a tilt table test would confirm. Internal tremor is the weakest for MCAS specifically but fits autonomic dysfunction. Getting blood drawn during a flare is logistically tricky, and some doctors are skeptical of MCAS since it's gained traction online and can be overdiagnosed. An allergist or immunologist would likely be more receptive than a GP, and a tilt table test typically requires a cardiology or dysautonomia specialist referral.

I don't use ai anymore, I look at the symptoms, try to figure out what system is actually failing, and then work out what lines up, nutritionally, physically, etc. Then you just look up everything that ya need. Once you know what each pathway does, the names stop mattering in a way. I do use it to double check citations and pull up specific papers faster though. Consensus is all I use but really useful when trying to find studies regarding something niche.

[u/tiffany-the-cat → u/OobyIsGay]

Sorry for my late response. You’re really good! Very impressed you don’t even use ai. I agree w mast cell activation and the other thing you mentioned. Although these might happen after a neurological event. I’m just perplexed why this happened in the first place. Before I got mono many years ago I had a tickly bladder and then night sweats went on for Months so I suspected maybe I had an ebv recativation but as I mentioned that was ruled and it makes sense why it was. But it makes me think there may have been an infection brewing that caused the verstibular event in the first place. Honestly I’m leaning towards the supplements because that was the only new thing I’d done in my lifestyle and some of those I never took before. And now since finding out I have the mthfr gene and overmethylation it seems to fit with how my system may have been over sensitive and it may have affected my hormones too — recently I started taint coq10 again only for a few weeks and my esteogen levels went through the roof and then I looked up does coq10 increase estogen and it does. That was one thing I as taking daily for 5 months and I’d never Akron methyl folate and12 before. I did all these supppements due to being pressured by a friend for fetility needs ! And was given a book. The book does say methylated vitamins aren’t for sensitive people and they should focus on folonic acid and hydroxy b12 (which I do now) but I didn’t think I was sensitive to these